ISOLATION OF NONOBESE DIABETIC MOUSE T-CELLS THAT RECOGNIZE NOVEL AUTOANTIGENS INVOLVED IN THE EARLY EVENTS OF DIABETES

Insulin-dependent diabetes mellitus (IDDM) is thought to result from c hronic, cell-mediated, autoimmune islet damage. Our aim was to identif y the earliest T-cell autoantigen in IDDM, reasoning that this antigen could be causally involved in the initiation of the disease. Identifi cation of the earliest beta-cell-specific autoantigen is extremely imp ortant in allowing advances in prevention and treatment of initial eve nts in the development of inflammatory insulitis that precedes beta-ce ll destruction and overt diabetes. Therefore, we analyzed the prolifer ative responses of peripheral T-cells from young, female nonobese diab etic (NOD) mice to extracts of pancreatic beta-cell lines. We were abl e to demonstrate that T-cells responsive to beta-cell antigens exist i n the peripheral lymphoid tissue of these mice in the absence of delib erate priming before the manifestation of histologically detectable in sulitis. T-cell lines and clones isolated from the peripheral lymphati c tissues of young, unimmunized, female NOD mice were also shown to re act with extracts of beta-cells. Fractionation of the beta-cell extrac ts showed that these T-cell clones recognized multiple beta-cell-speci fic autoantigens but none of the previously reported putative autoanti gens (glutamic acid decarboxylase [GAD]65, GAD67, Hsp65, insulin, ICA 69, carboxypeptidase-H, and peripherin). Thus, we can conclude that th ese responses are specific for novel beta-cell autoantigens. Finally, NOD T-cell proliferative responses were also seen to an extract of hum an islets suggesting potential shared antigenic determinants between h uman and mouse beta-cells. Our observation that human and murine beta- cell-specific antigens are conserved offers the possibility that ident ification of these murine autoantigens may lead to the discovery of th e human homologue. This will pave the way toward effective diagnosis a nd/or immunotherapy to prevent diabetes.